Inhibition of ceramide for the prevention and treatment of oral mucositis induced by antineoplastic drugs or radiation

ABSTRACT

Intervention for oral mucosal injury secondary to chemotherapy or radiation based on the inhibition in the synthesis of ceramide, blockage of its activity, or its digestion.

BACKGROUND OF THE INVENTION

[0001] Oral mucositis is a common, bothersome and dose-limiting sideeffect of many forms of cancer chemotherapy. The lesions that resultcause inflammatory and ulcerative changes that result in pain and lossof function. Consequently, patients with mucositis have difficultyeating and require pain medication. Since the frequency and severity ofmucositis are related to the choice and dose of the drug being used,oncologists may shy away from optimum agents and doses in order to avoidthis side effect. In addition, patients who receive myeloablativetherapy are at increased risk of local and systemic infection. Since themouth is normally rich in microorganisms, the loss of mucosal integritywhich accompanies mucositis at a time when patients' systemic defensesare compromised, results in the oral cavity being a major source ofinvading bacteria. In fact, the mouth is the most identifiable source ofsystemic bacteria in granulocytopenic cancer patients.

[0002] Patients who receive radiation therapy for tumors of the head andneck are also at high risk for oral mucositis. The frequency andseverity of mucosal injury is a function of the total dose and scheduleof radiation. Increasing the rate of radiation exposure results in ahigher incidence of mucositis. While the current trend of usingconcomitant chemotherapy with radiation results in a better tumoroutcome than radiation alone, these protocols are exceedinglystomatotoxic. Mucositis is often of such severity as to necessitate abreak in treatment to allow the tissue to recover. Such an interruptionin therapy reduces the overall anti-tumor effect of the radiation.

[0003] Historically mucositis was viewed as a process that was mediatedby epithelial damage. It was believed that the non-specific toxiceffects of chemotherapy or radiation resulted in DNA damage to therapidly dividing cells of the oral basal epithelium. This resulted incell death, atrophic changes of the mucosa, and ultimately, ulceration.However, four lines of observations suggested a biologic complexity thatextended beyond an epithelial etiology. First, electron microscopicobservations demonstrated that early damage was seen in both theendothelium and connective tissue underlying the epithelium and thesechanges preceded any noted in the epithelium. Second, administration ofpleotropic cytokines which attenuated levels of the pro-inflammatorycytokines, IL-1β and TNF-α, resulted in a reduction of mucositis inexperimental models. Third, high levels of the same pro-inflammatorycytokines were noted in the peripheral blood of patients withnon-hematologic toxicities associated with cancer chemotherapy. Andfourth, alteration of the local oral environment, particularly thebacterial load and saliva, modified the course of mucositis.

SUMMARY OF THE INVENTION

[0004] I believe that cells in the endothelium, connective and basalepithelium undergo apoptosis or cell death as mucositis progresses.While there are a number of mediators which influence this outcome, Iposit that the sphingolipid messenger ceramide is a major moleculardriver of cell death. Of particular relevance in this patient populationis the fact that ceramide may be generated in one of two ways; first,from sphingomyelin by activation of either neutral or acidicsphingomylinase; or second from dihydrosphosine following activation ofceramide synthase. TNF-α, already known to play a significant role inmucositis development, actives both the acidic and neutral forms ofsphingomylinase. Radiation may cause ceramide production by activationof the acidic form. Further, a number of chemotherapeutic drugs areknown activators of ceramide synthase.

[0005] I propose an intervention for oral mucosal injury secondary tochemotherapy or radiation based on the inhibition of the synthesis ofceramide, blockage of its activity or by its digestion. Using a rinseand swish technique, suspensions of the drug can be used by patientsimmediately prior to, and continuing throughout the course of theiractive treatment. Topical pastes and gels can also be used. Among thepossible agents are: Silymarin, a polyphenolic flavonoid derived frommilk thistle, which blocks ceramide activity;1-phenyl-2-decanoylaminon-3-morpholino-1-propanol and1-phenyl-2-hexadecanoylaminon-3-pyrrolidino-1-propanol, both of whichare inhibitors of glucosylceramide synthase; Scyphostatin, an inhibitorof neutral magnesium-dependent sphingomylinase; L-carnitine, aninhibitor of ceramide production; glutathione; and human milk bilesalt-stimulated lipase, which digests ceramide.

DETAILED DESCRIPTION

[0006] The therapeutic compositions of the invention are preferablyadministered to human patients to prevent or treat mucositis in the formof an oral rinse, as a topical paste, or as a gel. When used to help inthe prevention of mucositis, administration of the compositionspreferably will precede a given treatment with anti-neoplastic therapyby 1-2 days. Daily treatment can continue during the course ofanti-neoplastic treatment.

[0007] The concentrations of the therapeutic agents used in thecompositions of the invention will vary depending on which compound isbeing used, and can be determined routinely for each compound usingknown methods. The pharmaceutically acceptable carrier vehicles(liquids, gels, or pastes) are all well known as vehicles for otheroral/topical therapeutic compositions.

[0008] The active agents of the invention can be combined in thetherapeutic compositions with other active agents, includinganti-inflammatory agents such as ibuprofen, antimicrobial agents such astetracycline, and analgesics such as lidocaine.

[0009] Preferred compositions are liquid suspensions, which can berinsed and swished in the patient/s mouth, and gargled as well to ensureexposure of the active agent to the oropharynx. Preferably, this regimenis carried out daily over a fourteen day period to provide coveragethrough the first three phases of mucositis development.

[0010] Treatment according to the invention is particularly important inpatients who received multiple cycles of chemotherapy, e.g., patientssuffering from colorectal cancer, who receive monthly cycles ofchemotherapy. These patients are at particular risk for developingmucositis. Patients in this group begin dosing with a therapeuticcomposition of the invention two hours prior to administration ofchemotherapy, and then they continue topical application of themedication every four hours, while awake, for at least the next the 48hours. This regimen is repeated for each dosing cycle.

What is claimed:
 1. A method of treating, inhibiting, or preventingmucositis in a human patient, said method comprising administering tosaid patient an effective amount of a therapeutic composition comprisinga compound that either inhibits the synthesis of ceramide, blocks theactivity of ceramide, or degrades ceramide.
 2. The method of claim 1 ,wherein said therapeutic agent is in the form of an oral rinse, atopical paste, or a gel.
 3. The method of claim 1 , wherein saidcompound is selected from the group consisting of silymarin,1-phenyl-2-decanoylaminon-3-morpholino-1-propanol,1-phenyl-2-hexadecanoylaminon-3-pyrrolidino-1-propanol, Scyphostatin,L-carnitine, glutathione; human milk bile salt-stimulated lipase.